- Discovery of Sisunatovir (RV521), an Inhibitor of Respiratory Syncytial Virus Fusion
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RV521 is an orally bioavailable inhibitor of respiratory syncytial virus (RSV) fusion that was identified after a lead optimization process based upon hits that originated from a physical property directed hit profiling exercise at Reviral. This exercise encompassed collaborations with a number of contract organizations with collaborative medicinal chemistry and virology during the optimization phase in addition to those utilized as the compound proceeded through preclinical and clinical evaluation. RV521 exhibited a mean IC50 of 1.2 nM against a panel of RSV A and B laboratory strains and clinical isolates with antiviral efficacy in the Balb/C mouse model of RSV infection. Oral bioavailability in preclinical species ranged from 42 to >100% with evidence of highly efficient penetration into lung tissue. In healthy adult human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a significant reduction in viral load and symptoms compared to placebo.
- Cockerill, G. Stuart,Angell, Richard M.,Bedernjak, Alexandre,Chuckowree, Irina,Fraser, Ian,Gascon-Simorte, Jose,Gilman, Morgan S. A.,Good, James A. D.,Harland, Rachel,Johnson, Sara M.,Ludes-Meyers, John H,Littler, Edward,Lumley, James,Lunn, Graham,Mathews, Neil,McLellan, Jason S.,Paradowski, Michael,Peeples, Mark E.,Scott, Claire,Tait, Dereck,Taylor, Geraldine,Thom, Michelle,Thomas, Elaine,Villalonga Barber, Carol,Ward, Simon E.,Watterson, Daniel,Williams, Gareth,Young, Paul,Powell, Kenneth
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p. 3658 - 3676
(2021/04/12)
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- HETEROCYCLIC SPIRO-COMPOUNDS AS AM2 RECEPTOR INHIBITORS
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Disclosed are compounds of the formula (I) and pharmaceutically acceptable salts thereof: wherein HET, R1, R2, R3, R4, R5, L, L1, X1, X2, X3 and q are as defined herein. The compounds are inhibitors of adrenomedullin receptor subtype 2 (AM2). Also disclosed are the compounds for use in the treatment of diseases modulated AM2, including proliferative diseases such as cancer; pharmaceutical compositions comprising the compounds; methods for preparing the compounds; and intermediates useful in the preparation of the compounds.
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- HETEROCYCLIC SPIRO-COMPOUNDS AS AM2 RECEPTOR INHIBITORS
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Disclosed are compounds of the formula (I) and pharmaceutically acceptable salts thereof: wherein R1, R2, R4, R5, R6, R7, R8, R9, R10,Z, X1, X2, X3, L2, HET, n and q are as defined herein. The compounds are inhibitors of adrenomedullin receptor subtype 2 (AM2). Also disclosed are the compounds for use in the treatment of diseases modulated AM2, including proliferative diseases such as cancer; pharmaceutical compositions comprising the compounds; methods for preparing the compounds; and intermediates useful in the preparation of the compounds.
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- Calcitonin gene-related peptide (CGRP) receptor antagonist treatment of migraine
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Migraine is ranked as the sixth cause of years lost due to disability, with around 1.04 billion migraine sufferers globally. Triptans are considered the standard for acute migraine treatment, but an important number of migraineurs do not respond to them and these drugs are contraindicated in patients with cardiovascular disease. Migraine therapy is currently undergoing tremendous development, i.e., 5-HT1F receptor agonists (ditans), anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies, and small-molecule CGRP receptor antagonists (gepants). Ubrogepant (MK-1620) is a small-molecule, potent and selective CGRP receptor antagonist. In two phase III clinical trials (ACHIEVE I and II), ubrogepant showed, at 2 hours, significant percentages of pain freedom, and absence of the most bothersome symptoms in migraine patients. In a phase III study to assess the long-term (52-week) safety and tolerability, ubrogepant displayed good tolerability, and no signs of hepatic toxicity. In March 2019, the U.S. Food and Drug Administration accepted the new drug application (NDA) for ubrogepant for the acute treatment of migraine.
- Gras
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p. 869 - 879
(2020/01/21)
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- COMPOUNDS
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Disclosed are compounds of the formula (I) and pharmaceutically acceptable salts thereof: (I) wherein R1, R2, R3, R4, R5, R6, R8, R9, X, X1, X2, X3, L1 and n are as defined herein. The compounds are inhibitors of adrenomedullin receptor subtype 2 (AM2). Also disclosed are the compounds for use in the treatment of diseases modulated AM2, including proliferative diseases such as cancer; pharmaceutical compositions comprising the compounds; methods for preparing the compounds;and intermediates useful in the preparation of the compounds.
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- SPIRO-INDOLINES FOR THE TREATMENT AND PROPHYLAXIS OF RESPIRATORY SYNCYTIAL VIRUS INFECTION (RSV)
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Benzimidazoles of formula (I): wherein: one of X and Y is an N atom or a substituted C atom, and the other is CH; L is a single bond, C1-3 alkylene, C2-3 alkenylene or C2-3 alkynylene; R1 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 10-membered cycloalkyl, 5- to 10-membered heterocyclyl or 5- to 12- membered heteroaryl, each of which is unsubstituted or substituted; Z is halo, C1-6 haloalkyl, nitro, -CN, -N(R2)2, -OR2, -SR2, -S(=0)R2, or -S(=0)2R2; each R2 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, wherein said alkyl, alkenyl and alkynyl groups are unsubstituted or substituted; and m is 0 or 1; and the pharmaceutically acceptable salt thereof are inhibitors of RSV and can therefore be used to treat or prevent an RSV infection.
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- Conformationally constrained ortho- Anilino diaryl ureas: Discovery of 1-(2-(1′-Neopentylspiro[indoline-3,4′-piperidine]-1-yl)phenyl) -3-(4-(trifluoromethoxy)phenyl)urea, a potent, selective, and bioavailable P2Y1 antagonist
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Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y1 antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y12 antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the tert-butyl phenoxy portion of lead compound 1 and the subsequent discovery of a novel series of conformationally constrained ortho-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y1 antagonists with improved activity in functional assays and improved oral bioavailability in rats. Homology modeling and rat PK/PD studies on benchmark compound 3l will also be presented. Compound 3l was our first P2Y1 antagonist to demonstrate a robust oral antithrombotic effect with mild bleeding liability in the rat thrombosis and hemostasis models.
- Qiao, Jennifer X.,Wang, Tammy C.,Ruel, Réjean,Thibeault, Carl,L'Heureux, Alexandre,Schumacher, William A.,Spronk, Steven A.,Hiebert, Sheldon,Bouthillier, Gilles,Lloyd, John,Pi, Zulan,Schnur, Dora M.,Abell, Lynn M.,Hua, Ji,Price, Laura A.,Liu, Eddie,Wu, Qimin,Steinbacher, Thomas E.,Bostwick, Jeffrey S.,Chang, Ming,Zheng, Joanna,Gao, Qi,Ma, Baoqing,McDonnell, Patricia A.,Huang, Christine S.,Rehfuss, Robert,Wexler, Ruth R.,Lam, Patrick Y. S.
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p. 9275 - 9295
(2014/01/06)
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- IMIDAZOLINONE DERIVATIVES AS CGRP RECEPTOR ANTAGONISTS
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The present invention is directed to imidazolinone derivatives which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical comp
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Page/Page column 70-71
(2010/08/04)
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- CGRP RECEPTOR ANTAGONISTS
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Compounds of Formula (I) (wherein variables A1, A2, A3, ring-B, m, n, J, E1, E2, E3, R5, RPG and Y are as described herein), which are useful as antagonists of CGRP receptors, an
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Page/Page column 55-56
(2010/10/03)
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- 3- AND 6-QUINOLINES WITH N-ATTACHED HETEROCYCLIC CGRP RECEPTOR ANTAGONISTS
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Compounds of Formula (I): (where variables R1A, R1B, R2, R3, R4, A, and Z are as defined herein) which are useful as antagonists of CGRP receptors, and useful in the treatment or prevention of disease
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Page/Page column 55
(2010/04/03)
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- MONOCYCLIC CGRP RECEPTOR ANTAGONISTS
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The present invention is directed to compounds of the formula (I) : (wherein variables A1, A2, A3, A4, A5, A6, A7, A8, G1, G2, G3, G4, J, Q, Ea, Eb, Ec, R6, R7, RPG and Y are as described herein) which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
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- BRANCHED 3- AND 6-SUBSTITUTED QUINOLINES AS CGRP RECEPTOR ANTAGONISTS
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The present invention is directed to novel branched 3- and 6-substituted quinoline derivatives which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also
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- MONOCYCLIC ANILIDE SPIROLACTAM CGRP RECEPTOR ANTAGONISTS
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The present invention is directed to compounds of Formula I: I (where variables A1, A2, B, J, K, m, n, R4, R5a, R5b and R5c are as defined herein) useful as antagonists of CGRP receptors an
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- TRICYCLIC ANILIDE HETEROCYCLIC CGRP RECEPTOR ANTAGONISTS
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Compounds of formula I: wherein variables A1, A2, B, m, n, J, R4, G1, G2, G3 and Y are as described herein, which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
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- CARBOXAMIDE HETEROCYCLIC CGRP RECEPTOR ANTAGONISTS
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Compounds of formula I: I wherein variables A1, A2, B, m, n, J, R4, G1, G2, G3 and Y are as described herein, which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as mi
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- CONSTRAINED SPIROCYCLIC COMPOUNDS AS CGRP RECEPTOR ANTAGONISTS
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Compounds of formula I: I (wherein variables A1, A2, A3, G1, G2, G3, J, m, n, p, R1, R2, R3, R4 and Y are as described herein) which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is inv
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Page/Page column 32; 35; 36
(2008/12/06)
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- CGRP RECEPTOR ANTAGONISTS WITH TERTIARY AMIDE, SULFONAMIDE, CARBAMATE AND UREA END GROUPS
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Compounds of formula I: (I) (wherein variables A, m, n, J, Re, Rf, R4, Ea, Eb, Ec, RPG and Y are as described herein) which are antagonists of CGRP receptors and which are useful
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Page/Page column 93-94
(2008/12/08)
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- ARYL HETEROCYCLIC CGRP RECEPTOR ANTAGONISTS
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Compounds of formula I: I (wherein variables A1, A2, B, m, n, J, X, R4, G1, G2, G3 and Y are as described herein) which are antagonists of CGRP receptors and which are useful in the treatme
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Page/Page column 39; 44-45
(2008/12/08)
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- BICYCLIC ANILIDE HETEROCYCLIC CGRP RECEPTOR ANTAGONISTS
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Compounds of formula I: I (wherein variables A1, A2, B, m, n, J, R4, G1, G2, G3 and Y are as described herein) which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
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Page/Page column 52
(2008/12/08)
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- HETEROCYCLIC BENZODIAZEPINE CGRP RECEPTOR ANTAGONISTS
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Compounds of formula I: (where variables R2, R7, D, W, X, Y and Z are as described herein) which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
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Page/Page column 47; 61; 63
(2008/06/13)
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- SPIROLACTAM ARYL CGRP RECEPTOR ANTAGONISTS
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Compounds of formula (I): (wherein variables A1, A2, A3, A4, A5, A6, A7, E1, E2, E3, E4, E5, G1, G2, J and K are as described herein) which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
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Page/Page column 64
(2008/06/13)
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- SPIROHYDANTOIN TRICYCLIC CGRP RECEPTOR ANTAGONISTS
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Compounds of formula I: (wherein variables A1, A2, A3, A4, A5, A6, A7, B1, B2, B3, B4, D1, D2, E1, E2, E3, E4, E5, G1, G2, R6, T, U, V, W, X, Y and Z are as described herein) which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
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Page/Page column 89
(2008/06/13)
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- SPIROLACTAM TRICYCLIC CGRP RECEPTOR ANTAGONISTS
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Compounds of formula (I): (wherein variables A1, A2, A3, A4, A5, A6, A7, B1, B2, B3, B4, D1, D2, E1, E2, E3, E4, E5, G1, G2, J, K, T, U, V, W, X, Y and Z are as described herein) which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
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Page/Page column 56; 73
(2008/06/13)
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- Substituted monocyclic CGRP receptor antagonists
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Compounds of formula I: (wherein variables A1, A2, A3, A4, m, n, J, Q, R4, Ea, Eb, Ec, R6, R7, Re, Rf, RPG and Y are as described herein) which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
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Page/Page column 39
(2008/06/13)
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- SPIROLACTAM BICYCLIC CGRP RECEPTOR ANTAGONISTS
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Compounds of formula (I): (wherein variables A1, A2, A3, A4, A5, A6, A7, B, E1, E2, E3, E4, E5, G1, G2, J and K are as described herein) which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
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Page/Page column 64; 81
(2010/11/27)
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- MONOCYCLIC ANILIDE SPIROLACTAM CGRP RECEPTOR ANTAGONISTS
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The present invention is directed to compounds of Formula I: I (where variables A1, A2, B, J, K, m, n, R4, R5a, R5b and R5c are as defined herein) useful as antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the CGRP is involved, such as headache, migraine and cluster headache. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
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Page/Page column 39
(2008/06/13)
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- TRICYCLIC ANILIDE SPIROLACTAM CGRP RECEPTOR ANTAGONISTS
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The present invention is directed to compounds of Formula I: I (where A1, A2, B1, B2, B3, B4, D1, D2, J, K, T, U, V, W, X, Y, Z, R4, R5a, R5b, R5c, m and n are defined herein) useful as antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the CGRP is involved, such as headache, migraine and cluster headache. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
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Page/Page column 37; 49
(2010/10/20)
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- ARYL SPIROLACTAM CGRP RECEPTOR ANTAGONISTS
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The present invention is directed to compounds of Formula (I): where variables A1, A2, B, J, K, m, n, R4, R5a, R5b, R5c and X are as defined herein useful as antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the CGRP is involved, such as headache, migraine and cluster headache. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
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Page/Page column 37; 45-46
(2010/10/20)
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- BICYCLIC ANILIDE SPIROLACTAM CGRP RECEPTOR ANTAGONISTS
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The present invention is directed to compounds of Formula (I): (where variables A1, A2, B, J, K, m, n, R4, R5a, R5b and R5c are as defined herein) useful as antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the CGRP is involved, such as headache, migraine and cluster headache. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
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Page/Page column 38; 53
(2010/10/20)
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- CGRP RECEPTOR ANTAGONISTS
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The present invention is directed to compounds of Formula I: Formula I: I and Formula II: (where variables R1, R2, R3, R4, A, B, J, Q, T, V, W, X and Y are as defined herein) useful as antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the CGRP is involved, such as headache, migraine and cluster headache. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
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Page/Page column 52
(2010/11/08)
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- CGRP RECEPTOR ANTAGONISTS
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Compounds of Formula (I): and Formula (II): (where variables R2, R4, A, B, D, W, X, Y and Z are as defined herein) useful as antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the CGRP is involved, such as headache, migraine and cluster headache. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
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Page/Page column 74; 76-77
(2010/11/08)
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- CGRP RECEPTOR ANTAGONISTS
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Compounds of Formula I and formula II (where variables D, R2, R4, A, B, W, X, Y and Z are as defined herein) useful as antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the CGRP is involved,
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Page/Page column 52-53
(2010/11/08)
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- CGRP RECEPTOR ANTAGONISTS
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Compounds of Formula (I), (where variables R1, A, B, W, X, Y and Z are as defined herein) useful as antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the CGRP is involved, such as headache, migraine and cluster headache. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
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Page/Page column 63
(2010/11/23)
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